Mercurated allylurea derivatives and diuretics containing the same



Patented Apr. 21, 1953 MERCURATED .ALLYLUREA DERIVATIVES AN D'DIURETICS"CONTAINING THE SAME Ralph LI Rowland, Milwaukee, Wis.,

assignor t Lakeside.,Laboratories Inc., a corporation of Wisconsin No Drawing. Application January 18, 1951, Serial No. 206,711

This invention relates to mercurated allylurea derivatives and diuretics containingthe same.

This application is a continuation-in-part of my copcnding application, Serial No. 113,494, filed August 31, 1949, now'abandoned. l l l I In various types of heart diseases, particularly congestive hearttrouble, the patient becomes bloated due to sodiumin the form of salt and thus water gatheringin the tissues In order to relieve this condition, various compositions have been prescribed containing diuretic com-- pounds. ,These diuretics serve to excretewater and salt from the. kidneys'andthus from the tissues :50 that the heart condition is relieved. Many ,of thesiormer diuretic compounds were aromatic or aliphatic amines or amides, particularly aliphatic amines or amides. Inorganic mercury compounds have been used as diuretics for. many years, but only. recently have organic mercury compounds been used. The early organic mercury compounds were amines and amides containing a mercury atom. Most of these prior diuretic compounds, particularly of the mercury type, were dangerous to use as they sometimes caused death by stopping the heart. When they were injected into the veins or the muscles, they sometimes destroyed or at least caused severe irritation of the tissues. This was particularly true where: the injection into themuscle accidentally contacted fatty tissues.

The new compounds of this invention, which areparticularly useful as the active-ingredient indiuretic compositions, are mercurated allylurea compounds having essentially the structural formula:

R1 0 v Ra N NH--CH2 CHz HgX; Rz 1- iRiw wherein R1 and R2 are members of the class consisting of I alkylgroups; hydrogen atoms, and cycle-aliphatic groups "in WhichRr and Rzarc .12 Claims. (01. 167- 71) joined togetherto-iorm said group, R3 is a member of the class consisting of hydrogen "atoms and alkyl groups, at least one and not more than two of R1, R2 and Rs being a hydrogen atom, R4 is a member of the class consisting of hydrogen and an alkyl group, and X is a member of the class consisting or atoms of negative valence other than carbon atoms and groups including such ,an ,atom. bonded directly to. the mercury atom.

In the preferred compounds the alkyl "groups of R1 and R2 contain not more than six carbon atoms. Also in the preferred compounds, X is either halogen, hydroxyl, oxy-Eacyl, the residue of an acidic nitrogen compound having a replaceable hydrogen on the nitrogen atom, the residue of an alkyl thiol acid wherein the sulfur is bonded directly to the mercury atom the alkali metal salt ofthis acid residue or a theophylline residual Among the preferred compoundsof" this; vention having the above structural formula is the compound in which R1 is methyl, R2 is hydro gen, R3 is hydrogen, 'Riis methyl and X is 01110- rine. sun others are those which R2, R3, R4

and X are the same as those in the preceding compound and in which R1 is either ethyl, n-propyl, n-butylfn-hexyl and cyclohexyl. In other preferred compounds, R1 and R2 are joined to form apiperidyl group or a morpholyl group. In other preferred compounds, R1 and R2 are both either ethyl groups or n-loutyl groups. One of the compounds that is especially preferred is 3-chloromercuri 2 methoxy 2 methyl propylurea. In this compound R1 and R2 are each a hydrogen atom, R3 and R4 are each a group and X is a chlorine atom.

In preparing the new compounds of this invention substituted allyl ureasare used having the following structural formula:

where R1, R2 and R3 are as specified above. This compound is then reacted with a mercury compound tomake the new compoundsof this vention.

Still other new compounds of this invention,

which are particularly usefulasdihretics, are mercurated propylurea compounds with a mer cury substituent on theB-carbon atom and either hydroxyl or alkoxyl on the 2-carbon atom and having the following structural formula:

wherein R is either hydrogen or alkyl and X is either halogen, hydroxyl, oxy-a'cyl or the rest placeable hydrogen on the nitrogen is directly bondedto the mercuryatom. Of these compoundsit is preferred thattheR be an alkyl group containing froml to 5 carbon atoms. These compounds may also have a small l.

methyl proportion of a compound having the following structural formula:

Examples of the new compounds and their preparation are as follows:

To 23 g. of a 35% aqueous solution of methylamine was added g. of allylisocyanate. The mixture was concentrated at room temperature. The residue after crystallization from ethyl ether, melted at 4849 and weighed 3.0 g.

Analysis: Calcd. for CsHioNzOz N, 24.50- Found: N, 23.70.

To a solution of 2.5 g. of Nallyl-N'-methylurea in 50 cc. of methyl alcohol was added a solution of 6.4 g. of mercuric acetate in 100 cc. of methyl alcohol. After sixteen hours, the insoluble material was removed by filtration and a solution of 2.0 g. of sodium chloride in 20 ml. of water was added to the filtrate. After twenty hours, the white precipitate was collected by filtration, washed with water and crystallized from ethyl alcohol. The product melting at 176-177 weighed 1.8 g.

Analysis: Calcd. for CsH13N202HgClZ Hg, 52.62; N, 7.34. Found: Hg, 52.61; N, 7.13.

Example 2 C H NHCONHCH CH OCH CHgHgCl N- (3-chloromercuri-2-methoxypropyl -N-ethylurea To 33 g. of an aqueous solution of ethylamine (33%) was added 10 g. of allyl isocyanate. The residue after concentration at room temperature was crystallized from isopropylether. The N- allyl-N-ethylurea weighed 33 g. (20%) and melted at 79-80.

Analysis: Calcd. for Found: N, 21.35.

To a solution of 2.4 g. of N-allyl-N-ethylurea in 50 cc. of methyl alcohol was added a solution of 6.4 g. of mercuric acetate in 100 cc. of methyl alcohol. After twenty-four hours, the insoluble material was removed by filtration and a solution of 1.5 g. of sodium chloride in 20 cc. of Water was added to the filtrate. The solid which separated upon concentration of the solution at room temperature, was washed with water and crystallized from isopropyl alcohol. The recrystallized material, melting point 140-141", weighed 2.2 g.

Analysis: Calcd. for CvHnsNzOzHgCl: Hg, 50.75; N, 7.09. Found: Hg, 50.75; N, 6.76. 1

Example 3 n-C H NHCONHCH CH 0on crnn ci N- 3-ch1oromercuri-2-methoxypropyl) -N-n-propylurea To 20 g. of propyl amine in ml. of absolute ether was added 12.5 g. of allylisocyanate. The solution was concentrated at room temperature and the residue was crystallized from ethyl ether or from Skelly B. The recrystallized N-allyl- N'-propy1urea, melting at 96-97", weighed 5.0 g. (25%).

Analysis: Calcd. Found: N, 19.44.

Toa solution of 4.0 g. of N-allyl-N-propylurea in 50 cc. of methyl alcohol was added a solution of 8.0 g. of mercuric acetate in 100 ml. of methyl alcohol. After sixteen hours, the insoluble ma- Col-112N202 N, 2 1.86.

for C7H14N2O-t N, 19.72.

terial was removed by filtration and a solution of 2.0 g. of sodium chloride in 25 ml. of water was added to the filtrate. The solid which separated upon concentration at room temperature was washed with water and crystallized from isopropyl alcohol. The product melted at 1205-121 and weighed 5.0 g. (50%).

Analysis: Calcd. for CsHnNzOzHgCl! Hg, 49.01; N, 6.84. Found: Hg, 48.78; N, 7.22.

Example 4 n-C H NHCONH CHZCH (OCH (iH l-lgCl N- 3-chloromercuri-2methoxypropyl) -N'-n-butylurea From the reaction of allylisocyanate with In butylamine, at room temperature in anhydrous ether, N-allyl-N-butylurea was obtained in 40 3 yield. This product, after washing with Skelly-l3, melted at 62-64.

Analysis: Calcd. Found: N, 17.64.

By essentially the same technique used in the preceding examples, N-allyl-N-butylurea was methoXy-mercurated. The N-(E-chloromercuri- 2-methoxypropyl) -N-n-butylurea, after crystallization from ethyl alcohol, melted at 134435". Yield, 30%.

Analysis: Calcd. for C9H19N2O2HgCl: Hg, 47.06; N, 6.62. Found: Hg, 47.39; N, 6.76.

Example 5 11-C H NHCONHCHZCH (OCH CH HgC1 N- 3-chloromercuri-2-methoxypropyl) -N-nhexylurea for CsH1sN2OZ N, 17.87.

CroHzoNzO: N, 15.20.

Example 6 CH1OH2 NC ONHCHzCHOOHaCHzHgCl CHzCz N-3-chloromercuri-2methoxypropylcarbamylmorpholine From the reaction of allylisocyanate and morpholine in ether, N-allylcarbamylmorpholine, crystallized from isopropyl ether to a constant melting point at 131-132". Yield: 50%.

Anaylsis: Calcd. for CsHmNzOzI Found: N, 16.65.

By the method used in the preceding examples, N-allylcarbamylmorpholine was converted to N-3 chloromercuri 2 methoxypropylcarbamyl morpholine. The mercurial after crystallization from ethyl alcohol melted at 1125-1135. Yield: 46

Analysis: Calcd. for CsHnNzOsHgCl: Hg, 45.37; N, 6.41. Found Hg, 45.83; N, 6.53.

sample 7 CH2-C Hz CH2 NCONHCH2OH OCH3 CH2HO1 O HzC H1 N-S-chloromercuri-Z-methoxypropylcarbamylpiperidine N-allylcarbamylpiperidine, prepared by the reaction of allylisocyanate and piperidine in ether,

aasugsae waszcrysta-llized' from isopropyl other tea cen*-' Stan-t melting" point of 9U +91 i Yield: 30%.

To a solution of N-al lylcarhamylpiperidine in hotmetj-liyl alcohol Was-added a' mixtureof mer curicacetate; acetic acid and methyl alcchell After the reaction mixture Was heated-underreflux for one-hour,- -theinsoluble matenial wasremoved by filtration. A solution of sodium chloride in Water was .added to the filtrate and the mixture was concentrated at room temperature. The residue was Washed with water and with ethyl alcohol and recrystallized from isopropyl ether. The recrystallizedmaterial melted at 119-120".

Analysis: Calcd. for CH19N202Hg12 Hg, 46.08; N, 6.43. Found: Hg, 45185; N; 6147".

N-allylrN ,N. diethylu-rea. was. prepared by the reaction .of allYlisocyanate. and .diethylamine... The prodlQhdistilling atliltt-llilf at 1. was obtained in 65%ryield. n lal'lfin Analysis: Galcd: fcrrGafiigNzoz. N; 17193.- Round: N, 18.04.

To a solution of N-all yl-NQN'-diethylurea in methyl alcohol was-aditled a mixture of mercuricacetate, acetic acid and methyl alcohol. After one day, the insoluble material was removed by filtration and an aqueous solution of sodium chloride was added to the filtrate; The mixture" was concentrated at room temperature. The oily residue, N (Smhloromercuri-2-methoxypropyl I T',N-diethylurea, did not solidify.

Example 9 (mCQEI EN-CONHCHQCHGC-HEGHQH ot N- 3-chlocomercurianethoxypropyl).-N,N'-dibutylurea From the-reaction. of. dibutylanii-ne with. allylisocyanate, N allylvlalffiilkdibutylurea. was. ob..- tained. in 3.0% yield. The. product. boiled. at 11 1418.? at 1 mm Hg. 7i =1A5921 Analysis: Calcd. for. CrzHzrNzO: N, 13.19.. Found; N,.l3-.03:..

To. a. hot solution of} N-allylrNf';Nf.- dibuty1urea in. methyl. alcohol was addeda mixture sinner..- curic: acetate, acetic acid and methyl alcohol; After. the reactionimixture Washeated under 11efiux for sixteen hours, the insoluble materialrwas removedbyfiltratiom A solutionof sodiumch1oride in water was added to the filtrate and the mixture Was concentrated at room temperature. The oily residue, after Washing with Water and drying in vacuo over sulfuric acid, solidified. After Washing with Skelly Tithe solid melted at 69-70". Yield: 25%.

Analysis: Calcd. for CiaHz'zNzozHgCl: Hg, 41.85; N, 5 .84. Found: Hg, 41.25; N. 5.94.

the'rfltrate wasi-conoentrasteuiim scum! ime: r smear methallylurea. crystallization! dram ethyl acetate melted at'119-120'."1. Yield? 1 9d g;-

i'rhe: precipitate was. collect d byfiltration.

Example 11' O C Ha 3-ci1Ioromercuriizbmethnxy pmiiolunea cal'IuclNgogHg. M. Win-368 To a refluxing solution 0110'0 g. of allyl urea in 600 ml. of absolute methanol there was added with stirring asuspensiom .of..3-19-g'. of: mercuric acetate: in. 600 m1. of. absolute methanol and 60 ml. of glacial acetic acid; complete solution resulted. After 6' hours of refluxing the solution was cooled and clarified by filtration. To thisisoi utiom there. was added: .595 g; of; sodium chloride 240 ml. of watch. Aftenazzshortztime a heavy: white precipitate. settl'ezri out. This was filtered; washed; and? eluted; resulting; in 2511 g. (68 yieldl with: a 1E41i-1i429fi6. After orysta-llizafion from ethyl: alcohol; melted... at 149%-1 50% 61 l Example 12 If in place:- oil the sodium chloride of Example 1.1,.there .is us d sodium bromide. a pr ipita of the. bromo-m'ercuri compound results in 60% yield. It was recrystallized from" alcohol and melts at 161- 1 1 y Cale: 63 Hg? 48 .8% Found-l N, 5,5 13

3-hydroxymercuri-Z-methoxy-propylurea CEHQQN:OgZHEg .21345? Allyl urea wasvmercurated in methanolic solution with. mercuric. acletate. in. Example 11. After refiuxing,.the solution. was clarified and concentrated to a. viscous liquid. Two molar equi 0.3 a so ilti m o so um hydroxid were. .tliefres l'lfing solution: again" can:

estimated-w a viscous-liquid: on standing it solidi'fledf. The solid -wasgranulflted. by suspem 7 yield was 75% of white material, M. P. 181-182 C. Analysis: Calc: N, 8.03; Hg, 57.6. Found: N, 8.30; Hg, 57.2.

Example 14 HzN- -NH-CHQ-OHCHQHgOH 6H 3-hydroxymercuri-2-hydroxypropylurea 4 2O3Hg M. W.:335 To a solution of 80 g. of allyl urea in 180 ml. of hot water there was added a hot solution of 250 g. of mercuric acetate in 170 ml. of water and 48 ml. of acetic acid. The resulting mixture was refluxed for 1% hours. To one-fifth of the solution thus formed, there was added with cooling and stirring approximately 80 g. of 20% sodium hydroxide solution. A gummy precipitate resulted. The supernatant solution was decanted and an additional 20 g. of sodium hydroxide solution was added. A white precipitate formed; this was washed with water and then ethyl alcohol, whereupon it showed the following melting point: turns green at 140 0., black by 205 and becomes a black semi-fluid mass with gas evolution at ca. 230 C.

Analysis: Calc: N, 8.36; Hg, 60.0. N, 8.74; Hg, 60.3.

Found I Example O G O C H: HZN-JZ I NH-C H2CHC Hr-Hg-N C H; O O 0 H2 3-suecinimidomercuri-Z-methoxy-propylurea n m aOJIg M. W.=430

To a solution of 2.5 g. of succinimide in 50 ml. of water there was added 9 g. of 3-hydroxymercuri-2-methoxy-propylurea (Example 13).

The practically complete solution which resulated was clarified and the filtrate concentrated at room temperature. The resulting solid which precipitated was crystallized from ethyl alcohol and then melted at 159-169 C.

Analysis: Calc: N, 9.77; Hg, 46.7. Found: N, 9.59; Hg, 46.4.

Example 16 3-phthalimidomercuri-2-methoxypropylurea 13 15 3 4 M. W. 478

Found Example 17 To a refluxing solution of 85 g. of allyl urea in 500 ml. of absolute ethanol there was added 271 g. of mercuric acetate in 800 ml. of ethanol and .50 ml. of glacial acetic acid over a period of one hour. After refluxing an additional hr. the

' water was used.

N, 7.36; Hg, 52.7. Found:

Example 18 S-chloromercuri-2-n-butoxy-propylurea C8H17N2O2ClHg M. W. 409

In place of ethanol in Example 17, the reaction was run in normal butanol at approximately 70 C. and the resulting solution concentrated and sodium chloride solution added, there was obtained on further concentration, followed by crystallization from water, the corresponding n-butoxy analog, of M. P. -122 C.

Analysis: Cale: N, 6.85; Hg, 49.2. N, 6.84; Hg, 49.0.

Example 19 Found OCHa 3-ureido 2-methoXy-propy1-mercury-theophylline C H N 0 Hg M. W. 511

In place of the succinimide of Example 15, there was used an equimolecular amount of theophylline, solution was effected when hot The solution was clarified, cooled and concentrated at room temperature. Upon drowning in acetone a precipitate appeared and became granular on stirring. This was filtered, washed with acetone and then crystallized from ethyl alcohol, whereupon it melted at -182 C. Further crystallization raised the M. P. to 188-188 /2 C.

Analysis: Calc: Hg, 39.3. Found: Hg, 39.1.

Example 20 3-chloromercuri-2-isopropoxy-propylurea 7 15 zO2HgC1 M. W.:: 395

' tained.

Analysis: Calc: N, 7.09; Hg, 50.9. N, 7.17; Hg, 51.0.

Found 2 '0 Ha 3-acetoxymercuri-Z-methoxy-propylurea CqH N 0 HEg M. W. 391

Allylurea was mercurated in methanolic solution with mercuric acetate as in Example 1 1. The clarified solution was concentrated at room temperature to a viscous liquid. This on being allowed to stand slowly deposited a solid, but was too viscous to filter. Bytrituration with acetone a solid was obtained melting at 122 3 "C. This was crystallized from isopropyl alcohol and then melted at 126-127 c.

Analysis: Calc: N, 7.16; I-Ig, 51.4. N, 7.30; Hg. 51A. I

The invention described herein is also related to the copending application of Emmanuel Leon Foreman, Serial No."113,493., filedAugust 31, 1949. In this application also R1, R2 and R3 are each a hydrogen atom and Rs iseithe'r hydrogen or alkyl. In this copending application, X is an atom other than carbon and having a negative valence or a group including such an atom bonded directly'tothe mercury.

The new compounds are'used with the ordinary carriers, such as in aqueoiissolutions; as diuretics and may be injected either intravenously; sub cutaneously or intramuscularly. When so injected, there is noted a marked increase in urinary output. This increase ordinarily lasts about five hours after which the output of liquids returns to its normal level. In treating patients having large amounts of water and salt in the tissues, the injections are continued until a constant weight in the patient is obtained. After this constant weight has been obtained, no more need be given until such time as there is noted a marked weight increase. The new mercurated allylureas are non-toxic even when given in relatively large amounts and are superior to other prior mercury compounds in eliminating a greater amount of liquid and salt in a given time.

The foregoing detailed description is given for clearness of understanding only and no unnecessary limitations are to be understood therefrom, for some modifications will be obvious to those skilled in the art.

I claim:

1. The new compound having essentially the structural formula:

Found:

N NHCH:-J2-CH:HgX Rg R wherein the radical R, is selected from the class consisting of alkyl hydrogen alkyl N-, N, N-- alkyl hydrogen hydrogen CHI-CH2 OH2CH2 G g N- and 0 N- CHz-CH: CHz-Oz radicals, R3 is a member of the class consisting of hydrogen atoms and alkyl groups, R4 is a member of the class consisting of a hydrogen atom and alkyl groups, and X is a member of the class consisting of a halogen, a hydroxyl, an oxy-acyl, the residue of acidic nitrogen ompounds theophyume', 'S ucciniiiii'de, and p'hthal'ilrfid having a replaceable hydrogen on thenitrogenatom, the residue of an amyi thiol acid wherein the sulfur is bonded directly to me' mercurya; In, and the alkali metal salts or said thibl acid esidue, at least one and not more than two of Brits, and Rs being a hydrogen atom when X includes a sulfur atom linked to the mercury atom.

2. Thenew compound having essentially the structural formula:

H CH3 3. The new com-pound having essentially the structural formula:

4. The new compound having essentially the structural formula:

0 H N -Nn onz o=cm ngoi a tea. 5. The new compound having "essentially the structural formula:

6. The new compound having essentially the structural formula:

hydrogen /N-, /N, alkyl hydrogen CHz-C H;

CHa-CHz N-, and 0 N- CHr-C z cHr-cz radicals, R3 is a member of the class consisting of hydrogen atoms and a1ky1 groups, R4. is a member of the class consisting of a hydrogen atom and alkyl groups, and X is a member of the class consisting of a halogen, a hydroxyl, an oxy-acyl, the residue of acidic nitrogen compounds: theophylline, succinimide, and phthalimide, having a replaceable hydrogen on the nitrogen atom, the residue of an alkyl thiol acid wherein the sulfur is bonded directly to the mercury atom, and the alkali metal salts of said thiol acid residue, at

9. As a diuretic, a pharmaceutical carrier having associated therewith a compound having essentially the structural formula:

(H) CH3 N-CNHCHz-CHz-Hg(3l H CH3 10. As a diuretic, a pharmaceutical carrier having associated therewith a compound having essentially the structural formula:

11. As a diuretic, a pharmaceutical carrier having associated therewith a compound having essentially the structural formula:

12. As a diuretic, a pharmaceutical carrier having associated therewith a compound having essentially the structural formula:

wherein X is a theophylline residue.

RALPH L. ROWLAND.

References Cited in the me of this patent UNITED STATES PATENTS Number Name Date 2,208,941 iger et a1 July 23, 1940 2,315,817 Ruzicka Apr. 6, 1943 2,592,418 Halpern Apr. 8, 1952 OTHER REFERENCES Heilbron-Dictionary of Organic Chemistry, vol. 1, page 32, (1934) Lipschitz-J. Pharmacology and Experimental Therapeutics, 1944, pages 84-86, 93-4.

New and Non-Oificial Remedies, 1949, J. P. Lippincott 00., May 1949, pages 316-320.

Rowland et al.Jour. Amer. Chem. Soc., vol. '72, August 1950 #8, pages 3595-3598. 

1. THE NEW COMPOUND HAVING ESSENTIALLY THE STRUCTURAL FORMULA:
 7. AS A DIURETIC, A PHARMACEUTICAL CARRIER HAVING ASSOCIATED THEREWITH A COMPOUND HAVING ESSENTIALLY THE STRUCTURAL FORMULA: 